Walker, SL; Lockwood, DN (2008) Leprosy type 1 (reversal) reactions

and their management. Leprosy review, 79 (4). pp. 372-86. ISSN

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 Lepr Rev (2008) 79, 372 386

REVIEW

Leprosy Type 1 (reversal) reactions and their

management

STEPHEN L. WALKER & DIANA N.J. LOCKWOOD

Department of Infectious and Tropical Diseases, London School of
Hygiene and Tropical Medicine, Keppel St, London WC1E 7HT, UK

Accepted for publication 2 December 2008

Summary The type of leprosy that affects an individual depends on the immune
response mounted against the organism. This leads to a spectrum of disease which
may be complicated by immunological phenomena called reactions. Antimicrobial
chemotherapy is effective in treating the Mycobacterium leprae infection but up to
30% of individuals with borderline disease experience Type 1 reactions (T1Rs). T1Rs
are immunologically mediated episodes, localised in skin and nerves, which are a
major cause of nerve function impairment. Nerve function impairment may result in
disability and deformity. We review the frequency and features of Type 1 reactions.
The data from the limited number of randomised controlled trials of treatment are
discussed. These four randomised controlled trials were all conducted in south Asia.
The accepted treatment of T1Rs is with oral corticosteroids but there is no consensus
about the dose or duration of treatment due to the lack of data. One randomised
controlled trial showed that patients treated with a 5 month course of prednisolone
(total dose 231 g) were less likely to need additional prednisolone than those treated
with a 3 month course of prednisolone (total dose 294 g). This study did not use nerve
function as an outcome measure. The improvement in nerve function impairment
with steroid treatment is highly variable, with 33 73% of nerves recovering fully.
Optimal steroid regimes and alternative treatments need to be identified if the
disability associated with leprosy is to be minimised. Search strategy Papers for this
review were identified by repeated searches of the Cochrane Clinical Trials
Register, PubMed and LILACS with various combinations of the following search
terms leprosy, lepra, reaction, steroids, corticosteroids, reversal, Type 1,
Hansen*. Searches were complete to the end of November 2008.

Introduction

Type 1 reactions (T1Rs) are a major cause of nerve function impairment (NFI) in leprosy and
affect up to 30% of susceptible individuals.1 T1Rs may be a presenting feature of leprosy or

Correspondence to: Steve Walker, Department of Infectious and Tropical Diseases, London School of Hygiene
and Tropical Medicine, Keppel St, London WC1E 7HT (e-mail: drstevewalker@hotmail.com)

372 0305-7518/08/064053+15 $1.00 q Lepra

 Leprosy Type 1 reactions 373

occur during multidrug treatment (MDT) or even after it has been completed. Corticosteroids
have been used in the management of T1Rs and NFI for over 50 years but with limited data
from clinical trials. The response of NFI to corticosteroids is highly variable with 33 73% of
nerves recovering.2,3 We review the evidence for the use of corticosteroids in treating T1Rs
and highlight areas where future research is needed.

TYPE 1 (REVERSAL) REACTIONS

The Ridley-Jopling classification4 categorises leprosy patients into a spectrum with polar
tuberculoid and lepromatous forms and middle types of borderline tuberculoid (BT), mid
borderline (BB) and borderline lepromatous (BL) leprosy. Patients with different disease
types exhibit different immunological responses to M. leprae.5
A T1R is characterised by an increase in inflammation in skin lesions or nerves or both.
T1Rs predominantly affect the borderline states of leprosy. Borderline disease is a strong risk
factor for the occurrence of T1Rs1 but small numbers of patients with the polar forms of
leprosy may also experience T1Rs.6 Skin lesions become erythematous and/or oedematous
and may ulcerate. Oedema of the hands, feet and face can also be a feature of a reaction but
systemic symptoms are unusual.
The diagnosis is usually made clinically but a skin biopsy is sometimes used to help
support the diagnosis. Interestingly, even experienced pathologists may under diagnose
reaction in skin sections from patients with clinically apparent T1R.7 Important diagnostic
features appear to be epithelioid cell granuloma oedema, dermal oedema, the presence of
plasma cells and granuloma fraction. But standardised criteria for the histopathological
diagnosis of T1Rs are needed.
Neuritis is present if an individual has any of the following: spontaneous nerve pain,
paraesthesia, tenderness, or new sensory or motor impairment.8 Nerve pain, paraesthesia or
tenderness may precede nerve function impairment (NFI), which, if not treated rapidly and
adequately becomes permanent. NFI may arise in the absence of symptoms and may go
unnoticed by the patient silent neuropathy.
The detection of NFI is done clinically. Graded Semmes-Weinstein monofilaments
(or a ball-point pen) are used to detect sensory loss. Voluntary muscle testing is used to
assess motor nerve function. A recent study by van Brakel et al., using nerve conduction
studies and quantitative sensory testing, has demonstrated that individuals experiencing
neuritis, NFI or reactional episodes either alone or in combination have evidence of sub-
clinical neuropathy up to 12 weeks prior to clinically detectable changes.9 Individuals
who have WHO disability grades 1 and 2 at diagnosis are significantly more likely to
have severe T1Rs.10 T1Rs are frequently recurrent and this can lead to further nerve
damage.11 T1Rs can occur at any time but are frequently seen after starting multi-drug
therapy (MDT) or during the puerperium.12 Indian and Ethiopian cohort studies show
that patients continue to experience reactions and neuropathy in the third year after
diagnosis and beyond.9,13
A retrospective study of 1,026 leprosy patients from Brazil found that a greater proportion
of the 54 patients with HIV co-infection had BT leprosy compared with HIV negative leprosy
patients. The HIV positive group had a significantly greater number of reactions (type not
specified) at diagnosis than the HIV negative group but the cumulative rate of reactions in the
two groups was similar overall.14
374 S. L. Walker and D. N. J. Lockwood

T1Rs have been increasingly reported in individuals with HIV co-infection as part of an
immune reconstitution inflammatory syndrome following the commencement of anti-
retroviral therapy.15 The influence of CD4 counts, viral load and anti-retroviral therapy on
T1Rs and associated neuropathy requires investigation in well controlled studies.

PATHOPHYSIOLOGY AND IMMUNOLOGY OF TYPE 1 REACTIONS

T1Rs are delayed hypersensitivity reactions that occur predominantly in borderline forms
of leprosy.16 M. leprae antigens have been demonstrated in the nerves and skin of patients
experiencing T1Rs. The antigens were localised to Schwann cells and macrophages.17
A study of Brazilian patients with slit-skin smear negative single lesion paucibacillary
leprosy showed that individuals with M. leprae DNA detectable by PCR in the skin were
more likely to experience a T1R than those in whom M. leprae DNA was undetectable.18
Schwann cells express toll-like receptor (TLR) 2.19 M. leprae infection may lead to the
expression of MHC II on the surface of the cells and this may give rise to antigen
presentation which triggers CD4 lymphocyte killing of the cell mediated by cytokines
such as TNF.20
Ethiopian patients with a microsatellite polymorphism in the tlr2 gene had an increased
frequency of T1R. However, individuals with the single nucleotide polymorphism (SNP)
597C ! T in the tlr2 gene had a lower frequency of T1R.21 Having the SNP 1805T ! G in
the tlr1 gene has been associated with a decreased risk of leprosy T1R in Nepali patients.22
This polymorphism appears to lead to a loss of expression of the receptor on the surface of
peripheral blood monocytes.23
More TNF protein is detectable using immunohistochemical techniques in the skin and
nerves during T1Rs.24 T1Rs appear to be mediated via Th1 type cells and lesions in
reaction express the pro-inflammatory IFN-g, IL-12 and the oxygen free radical producer
inducible nitric oxide synthase.25 The expression of mRNA of various chemokines
including IL-8, monocyte chemoattractant protein 1 and RANTES is higher in the skin
during reaction.26
However, the levels of circulating cytokines do not reflect the local changes taking place
in the skin during T1Rs. Treatment of the reaction causes clinical improvement but changes
in the inflammatory cytokines lag behind by some considerable time and in some may remain
unchanged.27 A similar seemingly paradoxical finding has also been demonstrated in
tuberculous meningitis.28 This variation in the inflammatory activity within different
compartments is important to bear in mind when designing experiments to study T1Rs and
may help to explain why treatment is not always effective.
The inflammatory cytokines produced during a T1R may affect local conversion of
endogenous corticosteroids (the cortisol-cortisone shuttle) in the lesional skin of leprosy
patients with T1Rs.29 The gene expression of the enzyme 11b-hydroxysteroid
dehydrogenase Type 2 which converts the active cortisol back to inactive cortisone is
decreased in the skin of patients with T1R compared to non-reactional controls. This
supports the hypothesis that local endogenous active steroid levels are increased during
T1R in response to the marked inflammation that has been triggered but are insufficient
to suppress it.
 Leprosy Type 1 reactions 375
THE FREQUENCY OF TYPE 1 REACTIONS AND NEURITIS COMPLICATING
LEPROSY

There have been relatively few epidemiological studies of T1Rs or neuritis in leprosy. Table 1
summarises some of the reports of the frequency of T1Rs.
The large variation in these rates is due to the different methodologies used and the
changing definitions of paucibacillary and multibacillary categories.
301% of individuals with borderline leprosy in Nepal develop a T1R.11 Half of these
individuals have demonstrable new NFI. These figures are from a retrospective study
conducted at a leprosy referral centre and similar studies conducted in India have reported
T1R rates of 89% in a cohort from Hyderabad presenting in 1 year (1985) and followed for
almost 6 years, 107% in Orissa between 1992 and 2002 and 241% in Chandigarh over
15 years.6,30,31 The cumulative rate in Hyderabad was 24% for paucibacillary (tuberculoid
and borderline tuberculoid) patients in the 5 year period 1982 to 1987.32 198% (60 of 303) of
the ILEP Nerve Function Impairment and Reaction (INFIR) cohort had a T1R at
recruitment.8 Thirty nine per cent (74 of 188) experienced a reaction or NFI during the 2 year
follow up period. A T1R occurred in 10% (19 of 188) of individuals during the study period.9
The 12 individuals who were diagnosed with a T1R limited to the skin had demonstrable
sub-clinical nerve involvement using sensory nerve conduction and/or warm detection
thresholds (P. Nicholls, personal communication).
357% of a cohort of MB patients in Malawi experienced a T1R or a deficit in nerve
function;33 199% of individuals enrolled in a prospective study from a referral centre in
Thailand developed a T1R, each patient was followed for a minimum of 3 years after being
diagnosed with leprosy.34 A prospective hospital based study from Vietnam demonstrated a
prevalence of T1Rs of 291% in 237 patients.1 A retrospective study conducted in the field in
Bangladesh identified T1Rs in 88% of individuals.35 A prospective study in Bangladesh with
5 years follow up demonstrated an incidence of T1Rs of 17% in MB patients.36 A prospective
field study of 594 individuals with up to 10 years follow up from Ethiopia reported a rate of
T1Rs of 165%.13 The prospective study from Bangladesh suggests that nerve function
impairment and T1Rs occur more than 17 times more frequently in men than women.37
This finding needs further confirmation in other studies.

STUDIES OF TYPE 1 REACTIONS AND NEURITIS TREATED WITH

CORTICOSTEROIDS

There were few good data for making evidence-based treatment decisions about managing
T1Rs or NFI. This was highlighted by the Cochrane systematic review Corticosteroids for
treating nerve damage in leprosy by van Veen et al.38 Three randomised controlled trials
were included in the review. The sole trial which examined the effect of corticosteroids in
T1R did not fulfil the initial inclusion criteria of the review.
Table 2 summarises the published studies of prospective cohorts in which systemic
corticosteroids or other immunosuppressants were used to treat T1Rs and/or nerve
involvement due to leprosy. Studies that were not formal clinical trials were included if there
was a clearly stated clinical outcome. There are only four randomised studies all of which
were conducted in south Asia.
 376
Table 1. The frequency of Type 1 reactions

S. L. Walker and D. N. J. Lockwood

Frequency of Type 1 reactions
Number of Duration of follow up and/or nerve function
Location of study Type of study patients Type of leprosy (years) impairment (%)

PROSPECTIVE STUDIES
Ethiopia 13 Cohort study 594 New patients 611 165
Bangladesh 36 Cohort study 2664 Paucibacillary (PB) and PB 3 PB 09
Multibacillary (MB)
MB 5 MB 17
Naini and Faizabad, Cohort study 303 Multibacillary 2 198
India 8
Thailand 34 Cohort study 176 All newly diagnosed types 3 minimum 199
Vietnam 1 Casecontrol study 237 All types except indeterminate Not clear 291
Malawi*33 Randomized trial of MB MDT 305 Multibacillary Mean follow up 3 years 357
BI $2 at any site
RETROSPECTIVE STUDIES
Hyderabad, India 30 Leprosy research centre clinic 494 All types #6 89
records review
Orissa, India 31 Regional leprosy centre 942 Patients registered between Not clear 107
records review 19922002
Hyderabad, India*32 Leprosy research centre clinic 1226 Paucibacillary (Tuberculoid Not clear 24
records review and borderline tuberculoid
198287)
Chandigarh, India 6 Tertiary referral clinic records 2867 All types except pure neuritic 313 241 at presentation. 33 overall
review leprosy
Brazil 66 Leprosy clinic records review 162 Untreated slit skin smear Not clear 259
positive patients
11
Nepal Leprosy hospital clinic 386 Untreated patients except Mean 173 301
records review those with pure neuritic
leprosy

*
These studies used definitions of PB and MB leprosy which differ from the current WHO definitions.
Table 2. Prospective studies using steroids in Type 1 reactions and/or nerve function impairment.

Number
Author, Year, Country Type of study Entry criteria enrolled Intervention Outcome measures Conclusion

Marlowe, 2007, Open, uncontrolled Severe acute Type 1 43 12 weeks ciclosporin Skin and nerve score Variable improvement
Ethiopia, Nepal 54 reactions 5 mg/kg and in skin and nerve signs
prednisolone 40 mg for
first 5 days
Ciclosporin increased to Improvement in clinical High levels of
75 mg/kg if outcomes and relapse recurrence of reaction
deterioration particularly in Ethiopian
patients
46
Rao, 2006, India Double-blind Severe Type 1 334 3 prednisolone regimes: Amount of extra The 5 month regimes
randomised controlled, reactions 35 g over 5 months prednisolone required were equally effective
parallel group 231 g over 5 months and less additional
294 g over 3 months prednisolone was
required by these two
groups than by the 3
month group
Marlowe, 2004, Nepal 53 Randomised, controlled Type 1 reactions skin or 40 12 weeks azathioprine Skin signs, nerve Equally effective
skin and nerve and 8 weeks tenderness, sensory and
prednisolone compared motor testing and
to 12 weeks amount of extra
prednisolone alone prednisolone required
Richardus, 2003, Nepal, Randomised placebo NFI of 6 24 months 92 16 week standard Sensory and motor test No difference
Bangladesh 50

Leprosy Type 1 reactions

controlled, double blind duration prednisolone regime scores
van Brakel, 2003, Nepal, Randomized placebo Isolated mild sensory 75 16 week standard Improvement in No difference between
Bangladesh 67 controlled, double blind impairment prednisolone regime monofilament scores treated and untreated
groups
Saunderson, 2000, Prospective field Neuropathy including 594 Steroid regimes for PB Motor and sensory 73% of all neuropathy
Ethiopia 2 observation study nerve tenderness (12 weeks) and MB (24 testing and symptom given steroids responded
weeks) patients improvement fully in 73 patients with
no impairment at
diagnosis
Croft, 2000, Bangladesh 3 Prospective, open, NFI 132 16 week standard Improvement 33% of motor nerves and
uncontrolled prednisolone regime 37% of sensory nerves
fully recovered at 12
months

377
67% of nerves improved
 378
S. L. Walker and D. N. J. Lockwood
Table 2. continued
Number
Author, Year, Country Type of study Entry criteria enrolled Intervention Outcome measures Conclusion

Schreuder, 1998, Observation study Newly diagnosed 640 Not clear Nerve function Nerve damage at
Thailand 40 leprosy patients presentation improves in
only 44% compared to
82% improvement in
damage developing
whilst on treatment
Wilder-Smith, 1997, Prospective Skin signs obligatory 18 Prednisolone starting at Nerve function 212% improved sensory
Nepal 68 40 mg and tapered function and 13%
according to individual improved motor
response function
Nerve signs optional
Oedema/Fever
optional
Kiran, 1985, India 69 ?Prospective Open, Impaired VMT or ST 33 Semi-standardised Nerve score Good result in 74% of
uncontrolled prednisolone regime nerves
Touw-Langendijk, 1984, Open, uncontrolled Recent nerve function 36 6 month course of Sensory and motor 63% of affected nerves
70
Ethiopia loss prednisolone function (59/93) improved
Table 3. Retrospective reports of steroids in Type 1 reactions and/or nerve function impairment*

Author, Year, Country
31
Santaram, 2004, India
71
Bernink, 1997, Indonesia
van Brakel, 1996, Nepal 49 Retrospective
Lockwood, 1993, India 30
Becx-Bleumink, 1992,
Ethiopia 72
Kiran, 1991, India 73
Type of study Criteria for review Number analysed Measures Conclusion
Retrospective All reactions 101 Type 1 reactions of Satisfactory response 952% of all reactions had
942 cases satisfactory response
Retrospective field study Nerve function impairment 154 Improvement, the same or 75% of nerves improved in
in all types of reaction worse all types of reaction
Nerve function impairment 168 Comparison of nerve Up to 47% showed no
function at 3 and 6 months functional improvement
after steroids
Retrospective review of all Type 1 reaction 44 Type 1 reaction of 494 Improvement in symptoms 93% of skin lesions and
cases from 1985 cases and signs 50% of neuritic episodes
responded
Retrospective review of all All reactions 365 Type 1 reactions Recurrent reaction Approx a third of BL
reactions patients relapse as steroids
cut. 25% of nerves do not
improve
Nerve function loss
Retrospective #6 months of facial nerve 27 Degree of eyelid lag in mm 64% had a good response

Leprosy Type 1 reactions

damage with
lagophthalmos
(36 eyes)
74
Naafs, 1979, Ethiopia Retrospective review of Neuritis of selected 48 VMT deficit A longer course is better
reaction and neuritis patients than a short one

*
Checklist for patients starting high dose corticosteroids: Monitor blood pressure and weight at each visit; Urinalysis or blood glucose estimation; Gastric protection with H2
blocker or proton pump inhibitor; Treat those at risk of Strongyloides stercoralis with albendazole or ivermectin; Osteoporosis prevention.

379
380 S. L. Walker and D. N. J. Lockwood

Table 3 summarises reports of retrospective studies of the effect of corticosteroids on

T1Rs and/or nerve function impairment in patient series from Ethiopia, India, Nepal and
Indonesia.
Only limited conclusions can be drawn from these series. These studies suggest more
favourable responses to corticosteroids than the prospective data from the more rigorous
studies in Table 2. Despite this they clearly indicate a less than satisfactory response of T1Rs
or isolated nerve function impairment to corticosteroids.
Different methodologies employing different entry criteria and outcome measures have
made it difficult to compare studies. The grouping together of all individuals with T1R
regardless of whether new NFI is a feature of the reaction makes it difficult to assess the
impact on nerve function of the treatments being studied. The difficulty in recruiting
sufficient numbers of patients is a logistical problem that is best addressed using large multi-
centre studies.
The development of a clinical scale to measure the severity of reactions has been
undertaken.39 A clinical severity scale based on the scales used in the INFIR studies has been
validated in Bangladesh and Brazil (Walker et al. PLoS Negl Trop Dis in press). This
measurement tool will facilitate the comparison of subjects enrolled in a study and the
outcomes between studies. Further work is required to determine how useful a validated scale
is in reflecting response to treatment.
Studies have also used different features of nerve involvement such as nerve function
impairment and neuritis as entry criteria and outcome measures. Another difficulty has been
in trying to compare studies that use improvement as an outcome with those that use the more
stringent criterion of recovery. Some published studies have even looked at T1Rs and
erythema nodosum leprsoum (Type 2 reactions) together despite their different aetiology,
clinical presentation and response to treatment.
Several studies have indicated that some nerve function impairment will improve without
steroid therapy. This improvement may be spontaneous or attributable to MDT.2,3,40 The
prospective BANDS cohort included 69 individuals with NFI who should have received
prednisolone but did not. In these patients 33% of involved motor nerves and 62% of sensory
nerves had some degree of improvement at 12 months follow up.3 The AMFES cohort
included 141 individuals with NFI at the time of enrolment which had been present for longer
than 6 months and so were not treated with steroids. Between a quarter and a third of nerves
with this longstanding impairment fully improved during the long period of follow up.2
The effective killing of M. leprae by MDT may improve neuropathy which is due to direct
bacillary invasion of nerves and allow some axonal regeneration. The phenomenon of
spontaneous improvement in nerve function is another confounder in determining the size of
the effect of any intervention being studied. It would now be unethical to conduct a trial of the
effect of steroids compared to inactive placebo.
Women are under represented in the studies of T1Rs. The under representation of certain
groups affects many clinical trials worldwide.41 The results of trials may not be applicable if
the study population is not representative. The lack of recruitment of women is a cause for
concern. Gender inequalities may be more significant in leprosy as it is a highly stigmatising
disease.42 All the prospective studies outlined in Table 2 have recruited more men than
women with rates of female recruitment varying from 13 36%. Furthermore during the
puerperium it is very difficult to enrol women into trials.
 Leprosy Type 1 reactions 381
TREATMENT OF TYPE 1 REACTIONS

The treatment of T1Rs is aimed at controlling the acute inflammation, easing pain and
reversing nerve damage. MDT should be initiated in those presenting with a T1R or
continued in those who develop a reaction whilst on it. The use of adrenocorticotrophic
hormone in the management of leprosy reactions was first reported by Roche et al. in 1951.43
Corticosteroids bind to specific glucocorticoid receptors (GR) in the cytoplasm of the cell.
Once in the nucleus the GR-steroid complexes form dimers and bind to the promoter region
of steroid responsive genes known as glucocorticoid response elements (GRE). Activation of
GRE leads to the transcription of genes encoding anti-inflammatory mediators such as
annexin-1, MAP kinase phosphatase-1, I-kBa, secretory leukocyte protease inhibitor and
glucocorticoid-induced leucine zipper.44,45 Activated GR-steroid complexes may also
interact with the coactivator molecule and transcription factor complexes in the nucleus. This
reduces the production of proinflammatory cytokines. Corticosteroids, particularly in higher
concentrations, exert genomic effects (binding via the GR to DNA). They also have
nongenomic effects such as inhibiting transcription factors and destabilising mRNA.
Individuals with inflamed skin plaques, neuritis or nerve function impairment are
treated with oral corticosteroids. Different regimes have been employed in the
management of T1Rs. The practice at the Hospital for Tropical Diseases in
London is to use a starting dose of 30 40 mg of prednisolone tapered to zero over a
period of 5 6 months. A randomised study of three different prednisolone regimes
suggested that duration of treatment, rather than the starting dose of prednisolone, may be
more important in controlling T1Rs.46 Prednisolone 30 mg tapered slowly to zero over 20
weeks was superior to prednisolone 60 mg tapered over 12 weeks. Individuals with and
without nerve involvement were enrolled into the study. The primary outcome measures
were failure to respond to treatment and physician determined requirement for additional
prednisolone rather than improvement in nerve function or skin signs.
The role of a 4 month course of prophylactic steroids in the prevention of reactional
episodes, neuritis and nerve function impairment has been studied. The prednisolone had a
protective effect whilst patients were taking it but at 12 month follow up this effect had been
lost.47 The current WHO document: The Global Strategy for Further Reducing the Leprosy
Burden and Sustaining Leprosy Control Activities (2006 2010) states that Severe reversal
reactions should be treated with a course of steroids, usually lasting 3 6 months.48 Only
60% of individuals will show improvement in nerve function with 12 weeks of oral
prednisolone.49 Skin lesions will readily respond. The Global Strategy also states that
reactions requiring steroids should be referred to a specialist unit.
There is a consensus amongst leprologists that the use of steroids in nerve function
impairment is not worthwhile if the impairment has been present for more than 6 months.
This view is supported by the TRIPOD 3 study 50 which did not demonstrate any significant
improvement of nerve function present for longer than 6 months with prednisolone compared
to placebo.
A trial in which individuals with ulnar neuritis were randomised to either 6 weeks
prednisolone or medial epicondylectomy and 6 weeks prednisolone demonstrated
improvement in nerve function in both groups but did not show any added benefit of
surgery.51 A study from Senegal in 31 patients with neuritis who were treated with prednisone
for 6 months did not demonstrate any additional benefit of early surgery in those nerves
randomised to receive a decompression procedure and epineurotomy.52
382 S. L. Walker and D. N. J. Lockwood

Azathioprine in combination with an 8 week course of prednisolone was as effective as a

12 week course of prednisolone in the management of T1Rs in a pilot study in Nepal.53
Ciclosporin has been used in pilot studies in Nepal and Ethiopia with some success.54
There is no evidence to guide physicians in the optimal use of immunosuppression to
manage T1Rs affecting HIV positive individuals. A Ugandan study of patients with T1Rs
reported a similar response to steroids in the HIV infected and non-infected groups.55 The
current treatment of T1Rs in HIV infected individuals is with corticosteroids just as in
uninfected patients. The reported cases of T1Rs in co-infected individuals, whether ART
related or not, have all used corticosteroids. One individual required the introduction of
azathioprine to control repeated relapses of his steroid dependent T1R.56
An international workshop on neuropathology in leprosy produced a consensus report
which outlines research priorities in improving the understanding and management of nerve
damage. Many of these are relevant to T1Rs including the identification of markers of
reaction, large randomised controlled trials of corticosteroids (including patient tailored
regimens), alternative drug treatments and surgery.57 (Figure 1)

Figure 1. Checklist for patients starting high dose corticosteroids.

CONCERNS ABOUT THE USE OF CORTICOSTEROIDS

The risks associated with the administration of any drug are a concern. The use of potent
immunosuppressants is potentially problematic in areas endemic for severe infections such as
tuberculosis. Immunosuppression may also make infective conditions such as strongyloi-
diasis worse.58 The First European Workshop on Glucocorticoid Therapy designated doses of
prednisone between . 30 mg and # 100 mg as high doses which are associated with severe
side effects if used long term. This group also considers that side effects are considerable and
dose dependent at medium doses of between . 75 mg and # 30 mg.59
There is little evidence concerning the long term sequelae of corticosteroids used to treat
patients with T1Rs. Corticosteroids cause bone demineralisation leading to osteoporosis. This
is a dose dependent phenomenon and the rate of loss of bone mineral density is considerable
in the first 6 months of steroid therapy.60 Men with leprosy are at increased risk of
osteoporosis and this is associated with hypogonadism.61 The role of previous corticosteroid
therapy in exacerbating the osteoporosis affecting people who have had leprosy has not been
assessed. Osteoporosis may become increasingly important if longer courses of steroids are
conclusively proven to be superior in the management of T1Rs. At the Hospital for Tropical
Diseases patients taking prednisolone for T1Rs are also prescribed calcium carbonate and
cholecalciferol which they take until they no longer require corticosteroids. Studies are
required to assess both the extent of bone demineralisation in leprosy patients treated with
steroids and interventions that mitigate it.
 Leprosy Type 1 reactions 383

Diabetes and hyperglycaemia may occur during treatment with low doses of
corticosteroids. A case-controlled study of patients in a Medicaid programme in the USA
showed that at low steroid doses hypoglycaemic agents may be required.62 In a large series of
581 Indian patients with T1R, 22% developed diabetes requiring an oral hypoglycaemic
agent during the initial phase of treatment with corticosteroids.63 Cataracts are associated
with corticosteroid use but may also complicate leprosy (particularly MB disease) per se.
Cataract was identified in 4% of individuals treated for T1R by Sugumaran but all of these
patients had been on steroids for more than 12 months.63 Age-related cataract is now the
commonest cause of blindness in leprosy affected people.64
Analysis of the adverse events attributable to prednisolone in the three TRIPOD trials
suggests that the drug is safe when used under field conditions in standardised regimens.65
The trials used a total prednisolone dose of 196 g and 252 g. The steroid treated group were
significantly more likely to experience minor adverse events but there was no difference in
the likelihood of major adverse events between the prednisolone and placebo groups. Three
hundred of the 815 patients enrolled in the three studies were followed for 24 months and
none developed tuberculosis or hypertension during that time.
The adverse effect of additional immunosuppression in HIV positive patients with T1Rs
is an obvious concern but there is no evidence to inform decisions about dose and duration of
treatment in this group.

Conclusion

Systemic corticosteroids are the mainstay of treatment of T1Rs although conclusive evidence
of their efficacy is lacking. The optimal dose and duration of treatment with steroids is still
unclear although there is evidence that suggests prolonged therapy improves outcome. The
controlled trial that gives most weight to this argument did not use nerve function as an
outcome measure.
There is no evidence about the degree of benefit attributable to corticosteroids or the
degree of nerve damage that will respond. There is a real need for large trials to identify the
optimal steroid regime in T1Rs. These studies need to be well controlled and representative.
The role of other drugs in the management of reactions and nerve function impairment
also needs to be investigated. The optimal use of these either alone or in conjunction with
corticosteroids needs to be more clearly defined.
The role of surgery in the management of NFI needs to be better defined, and further
investigation of sub-clinical changes in nerve function prior to and during T1R is warranted.

Conflict of interests

None, and neither of the authors were involved in the editorial process for this manuscript,
which was edited by Professor Anthony Bryceson.

Acknowledgements

Dr Walker is supported by grants from LEPRA, the American Leprosy Mission, the Special
Trustees of the Hospital for Tropical Diseases, London and the Geoffrey Dowling Fellowship
of the British Association of Dermatologists.
384 S. L. Walker and D. N. J. Lockwood

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